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  51th ICAAC
Chicago, IL
September 17-20, 2011
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Novel Boehringer-Ingelheim Integrase Inhibitor Retains Full Activity Against Raltegravir-Resistant Virus
  51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago

Mark Mascolini

Four reports at this meeting spelled out early findings on BI 224436, an HIV integrase inhibitor with a mechanism different from that of the "tegravir" strand-transfer integrase inhibitors. This novel agent, being developed by Boehringer Ingelheim, binds to a highly conserved allosteric pocket of the integrase catalytic core--not to the catalytic site itself. LEDGF, a host cell factor important for HIV replication, binds to the same site. Because of this novel mechanism, integrase inhibitors like 224436 are expected to have resistance profiles different from strand-transfer integrase inhibitors. Complete data for these four studies is online at the NATAP links listed in the references below.

Phenotypic analysis of 40 recombinant viruses containing integrase from clinical isolates resistant to raltegravir determined that all 40 remained susceptible to 224436 with an average 50% effective concentration (EC50) of 26 +/- 16 nM and an average fold change in EC50 relative to wild-type (nonmutant) virus of 1.4 +/- 0.8 [1]. In contrast, raltegravir and elvitegravir had more than a 260-fold change in EC50 against these recombinant viruses.

These investigators also tested 224436 against HIV-1 isolates from 100 US and 100 European people naive to antiretroviral therapy [1]. Average EC50 and EC95 values for 224436 were 14 +/- 13 nM and 39 +/- 30 nM. Against these same viral isolates, average EC50 for raltegravir was 6.7 +/- 1.4 nM and average EC95 78 +/- 18 nM.

A study in healthy male volunteers yielded results indicating that once-daily dosing with 224436 "may be feasible," the investigators proposed [2]. This first-in-human double-blind placebo-controlled trial tested a single oral dose of 6.2, 12.5, 25, 50, 100, or 200 mg of 224436. In each dose group, 6 men took 224436 and 2 took placebo. All study participants were 21 to 50 years old and had a body mass index between 18.5 and 29.9 kg/m(2).

Maximum concentration (Cmax) and three area under the concentration-time curve (AUC) measures increased in a dose-proportional manner from 6.2 to 200 mg. Between-person variability for these parameters was low, with geometric coefficients of variation ranging from 13.1% to 31.5% for Cmax and from 20.2% to 31.7% for AUC 0-infinity. Absorption was rapid, with a median time to maximum concentration of 0.5 h in each dose group (overall range 0.25 to 1.5 h). Arithmetic mean terminal elimination half life ranged from 6.38 to 7.85 h across the 6 doses.

The investigators determined that the 100-mg dose provided the geometric mean 24-hour concentration (496 nmol/L, range 314 to 867) closest to the target minimum concentration of 500 nmol/L.

Mild adverse events included headache in 1 person, upper abdominal pain in 1, and oral paresthesia (tingling or numbness) in 2.

Boehringer Ingelheim scientists used a hollow-fiber infection model and pharmacokinetic modeling to project an optimal dose of 224436 in humans [3]. In the hollow-fiber system, this novel integrase inhibitor had an EC50 of 12 nM. At 39 nM 224436 inhibited more than 90% of virus. The investigators used these results and human PK data on the 100-mg dose [2] in Monte Carlo simulations to predict that the 100-mg dose will suppress replication with more than 90% probability for 200 HIV-1 clinical isolates studied.

Preclinical analysis of 224436 determined that this agent has EC50s ranging from 4 to 15 nM against HIV-1 lab strains [4]. CC50 (cell toxicity) values for 224436 exceeded 90 uM in peripheral blood mononuclear cells. Exposure to 50% human serum provoked only a 2.2-fold shift in antiviral potency.

So-called ADME (absorption, distribution, metabolism, and excretion) properties included a favorable metabolic profile, low potential for interaction with CYP3A4 and CYP2DG drug-metabolizing enzymes, and high permeability. Cell-based antiviral assays indicated that 224436 has an additive effect with agents in all current antiretroviral classes, including strand-transfer integrase inhibitors.


1. Fenwick C, Bethell R, Quinson A, et al. BI 224436, a non-catalytic site integrase inhibitor, is a potent inhibitor of the replication of treatment-naive and raltegravir-resistant clinical isolates of HIV-1. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Abstract F1-1370. http://www.natap.org/2011/ICAAC/ICAAC_34.htm.

2. Aslanyan S, Ballow C, Sabo JP, et al. Safety and pharmacokinetics (PK) of single rising oral doses of a novel HIV integrase inhibitor in healthy volunteers. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Abstract AI-1725. http://www.natap.org/2011/ICAAC/ICAAC_35.htm.

3. Brown AN, McSharry J, Kulawy R, et al. Pharmacodynamics of BI 224436 for HIV-1 in an in vitro hollow fiber infection model system. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Abstract A1-1726. http://www.natap.org/2011/ICAAC/ICAAC_33.htm.

4. Yoakim C , Amad M, Bailey MD, et al. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic site integrase inhibitor. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Abstract F1-1369. http://www.natap.org/2011/ICAAC/ICAAC_32.htm.